Preparation of 4-amino-thiazoles and 3-amino-1,2,4-thiadiazoles and their use as allosteric modulators of metabotropic glutamate receptors

ABSTRACT

The present invention relates to novel compounds of Formula (I), wherein M, P, X, A and (B) n  are defined as in Formula (I); invention compounds are modulators of metabotropic glutamate receptors—subtype 4 (“mGluR4”) which are useful for the treatment or prevention of central nervous system disorders as well as other disorders modulated by mGluR4 receptors. The invention is also directed to pharmaceutical compositions and the use of such compounds in the manufacture of medicaments, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR4 is involved.

SUMMARY OF THE INVENTION

The present invention relates to novel compounds of Formula (I), whereinM, P, X, A and (B)_(n) are defined as in Formula (I); inventioncompounds are modulators of metabotropic glutamate receptors—subtype 4(“mGluR4”) which are useful for the treatment or prevention of centralnervous system disorders as well as other disorders modulated by mGluR4receptors. The invention is also directed to pharmaceutical compositionsand the use of such compounds in the manufacture of medicaments, as wellas to the use of such compounds for the prevention and treatment of suchdiseases in which mGluR4 is involved.

BACKGROUND OF THE INVENTION

Glutamate is the major amino-acid transmitter in the mammalian centralnervous system (CNS). Glutamate plays a major role in numerousphysiological functions, such as learning and memory but also sensoryperception, development of synaptic plasticity, motor control,respiration and regulation of cardiovascular function. Furthermore,glutamate is at the center of several different neurological andpsychiatric diseases, where there is an imbalance in glutamatergicneurotransmission.

Glutamate mediates synaptic neurotransmission through the activation ofionotropic glutamate receptor channels (iGluRs), namely the NMDA, AMPAand kainate receptors which are responsible for fast excitatorytransmission (Nakanishi et al., (1998) Brain Res. Rev., 26:230-235).

In addition, glutamate activates metabotropic glutamate receptors(mGluRs) which have a more modulatory role that contributes to thefine-tuning of synaptic efficacy.

The mGluRs are G protein-coupled receptors (GPCRs) withseven-transmembrane spanning domains and belong to GPCR family 3 alongwith the calcium-sensing, GABAb and pheromone receptors.

The mGluR family is composed of eight members. They are classified intothree groups (group I comprising mGluR1 and mGluR5; group II comprisingmGluR2 and mGluR3; group III comprising mGluR4, mGluR6, mGluR7 andmGluR8) according to sequence homology, pharmacological profile andnature of intracellular signalling cascades activated (Schoepp et al.,(1999) Neuropharmacology, 38:1431-1476).

Glutamate activates the mGluRs through binding to the largeextracellular amino-terminal domain of the receptor, herein called theorthosteric binding site. This activation induces a conformationalchange of the receptor which results in the activation of the G-proteinand intracellular signalling pathways.

In the central nervous system, mGluR4 receptors are expressed mostintensely in the cerebellar cortex, basal ganglia, sensory relay nucleiof the thalamus and hippocampus (Bradley et al., (1999) Journal ofComparative Neurology, 407:33-46; Corti et al., (2002) Neuroscience,110:403-420). The mGluR4 subtype is negatively coupled to adenylatecyclase via activation of the Gαi/o protein, is expressed primarily onpresynaptic terminals, functioning as an autoreceptor or heteroreceptorand activation of mGluR4 leads to decreases in transmitter release frompresynaptic terminals (Corti et al., (2002) Neuroscience, 110:403-420;Millan et al., (2002) Journal of Biological Chemistry, 277:47796-47803;Valenti et al., (2003) Journal of Neuroscience, 23:7218-7226).

Orthosteric agonists of mGluR4 are not selective and activate the otherGroup III mGluRs (Schoepp et al., (1999) Neuropharmacology,38:1431-1476). The Group III orthosteric agonist L-AP4 was able toreduce motor deficits in animal models of Parkinson's disease (Valentiet al., (2003) J. Neurosci., 23:7218-7226) and decrease excitotoxicity(Bruno et al., (2000) J. Neurosci., 20; 6413-6420) and these effectsappear to be mediated through mGluR4 (Marino et al., (2005) Curr. TopicsMed. Chem., 5:885-895). In addition to L-AP4, ACPT-1, another selectivegroup III mGluR agonist has been shown to caused a dose-and-structuredependant decrease in haloperidol-induced catalepsy and attenuatedhaloperidol-increased Proenkephalin mRNA expression in the striatum(Konieczny et al., (2007) Neuroscience, 145:611-620). Furthermore, Lopezet al. (2007, J. Neuroscience, 27:6701-6711) have shown that bilateralinfusions of ACPT-I or L-AP4 into the globus pallidus fully reversed thesevere akinetic deficits produced by 6-hydroxydopamine lesions ofnigrostriatal dopamine neurons in a reaction-time task without affectingthe performance of controls. In addition, the reversal ofhaloperidol-induced catalepsy by intrapallidal ACPT-1 was prevented byconcomitant administration of a selective group III receptor antagonist(RS)-alpha-cyclopropyl-4-phosphonophenylglycine. The opposite effectsproduced by group III mGluR activation in the SNr strongly suggest arole of mGluR4 rather than other mGluR receptor sub-types in normalizingbasal ganglia activity (Lopez et al. 2007).

These results suggest that, among mGluRs subtypes, mGluR4 is believed tobe the most interesting novel drug target for the treatment ofParkinson's disease (for a review see Conn et al., (2005) Nature ReviewNeuroscience, 6:787-798).

Symptoms of Parkinson's disease appear to be due to an imbalance in thedirect and indirect output pathways of the basal ganglia and reductionof transmission at the inhibitory GABAergic striato-pallidal synapse inthe indirect pathway may result in alleviation of these symptoms (Marinoet al., (2002) Amino Acids, 23:185-191).

mGluR4 is more abundant in striato-pallidal synapses than instriato-nigral synapses, and its localization suggests function as apresynaptic heteroreceptor on GABAergic neurons (Bradley et al., (1999)Journal of Comparative Neurology, 407:33-46) suggesting that selectiveactivation or positive modulation of mGluR4 would decrease GABA releasein this synapse thereby decreasing output of the indirect pathway andreducing or eliminating the Parkinson's disease symptoms. Classicaltreatment of Parkinsonism typically involves the use of levodopacombined with carbidopa (SINEMETT™) or benserazide (MADOPAR™). Dopamineagonists such as bromocriptine (PARLODEL™), lisuride and pergolide(CELANCE™) act directly on dopamine receptors and are also used for thetreatment of Parkinsonism. These molecules have the same side-effectprofile as levodopa.

A new avenue for developing selective compounds acting at mGluRs is toidentify molecules that act through allosteric mechanisms, modulatingthe receptor by binding to a site different from the highly conservedorthosteric binding site.

Positive allosteric modulators of mGluRs have emerged recently as novelpharmacological entities offering this attractive alternative. This typeof molecule has been discovered for mGluR1, mGluR2, mGluR4, mGluR5,mGluR7 and mGluR8 (Knoflach F. et al. (2001) Proc. Natl. Acad. Sci.USA., 98:13402-13407; Johnson M. P. et al., (2002) Neuropharmacology,43:799-808; O'Brien J. A. et al., (2003) Mol. Pharmacol., 64:731-740;Johnson M. P. et al., (2003) J. Med. Chem., 46:3189-3192; Marino M. J.et al., (2003) Proc. Natl. Acad. Sci. USA, 100:13668-13673; Mitsukawa K.et al., (2005) Proc. Natl. Acad. Sci. USA, 102(51):18712-18717; WilsonJ. et al., (2005) Neuropharmacology, 49:278; for a review see Mutel V.,(2002) Expert Opin. Ther. Patents, 12:1-8; Kew J. N., (2004) Pharmacol.Ther., 104(3):233-244; Johnson M. P. et al., (2004) Biochem. Soc.Trans., 32:881-887; recently Ritzen A., Mathiesen, J. M. and Thomsen C.,(2005) Basic Clin. Pharmacol. Toxicol., 97:202-213).

In particular molecules have been described as mGluR4 positiveallosteric modulators (Maj et al., (2003) Neuropharmacology, 45:895-906;Mathiesen et al., (2003) British Journal of Pharmacology,138:1026-1030). It has been demonstrated that such molecules have beencharacterized in in vitro systems as well as in rat brain slices wherethey potentiated the effect of L-AP4 in inhibiting transmission at thestriatopallidal synapse. These compounds do not activate the receptor bythemselves (Marino et al., (2003) Proc. Nat. Acad. Sci. USA,100:13668-13673). Rather, they enable the receptor to produce a maximalresponse to a concentration of glutamate or the Group III orthostericagonist L-AP4 which by itself induces a minimal response.

PHCCC, a positive allosteric modulator of mGluR4 not active on othermGluRs (Maj et al., (2003) Neuropharmacology, 45:895-906), has beenshown to be efficacious in animal models of Parkinson's disease thusrepresenting a potential novel therapeutic approach for Parkinson'sdisease as well as for other motor disorders and disturbances (Marino etal., (2003) Proc. Nat. Acad. Sci. USA, 100:13668-13673),neurodegeneration in Parkinson's disease (Marino et al., (2005) Curr.Topics Med. Chem., 5:885-895; Valenti et al., (2005) J. Pharmacol. Exp.Ther., 313:1296-1304; Vernon et al., (2005) Eur. J. Neurosci.,22:1799-1806, Battaglia et al., (2006) J. Neurosci., 26:7222-7229), andneurodegeneration in Alzheimer's disease or due to ischemic or traumaticinjury (Maj et al., (2003) Neuropharmacology, 45:895-906).

PHCCC also has been shown to be active in an animal model of anxiety(Stachowicz et al., (2004) Eur. J. Pharmacol., 498:153-156). Previously,ACPT-1 has been showed to produce a dose-dependent anti-conflict effectafter intrahippocampal administration and anti-depressant-like effectsin rats after intracerebroventricular administration (Tatarczynska etal., (2002) Pol. J. Pharmacol., 54(6):707-710).

Activation of mGluR4 receptors which are expressed in α- and F-cells inthe islets of Langerhans inhibits glucagon secretion. Molecules whichactivate or potentiate agonist activity of these receptors may be aneffective treatment for hyperglycemia, one of the symptoms of type 2diabetes (Uehara et al., (2004) Diabetes, 53:998-1006).

The β-chemokine RANTES is importantly involved in neuronal inflammationand has been implicated in the pathophysiology of multiple sclerosis.Activation of Group III mGluRs with L-AP4 reduced the synthesis andrelease RANTES in wild-type cultured astrocytes, whereas the ability ofL-AP4 to inhibit RANTES was greatly decreased in astrocyte cultures frommGluR4 knockout mice (Besong et al., (2002) Journal of Neuroscience,22:5403-5411). These data suggest that positive allosteric modulators ofmGluR4 may be an effective treatment for neuroinflammatory disorders ofthe central nervous system, including multiple sclerosis and relateddisorders.

Two different variants of the mGluR4 receptor are expressed in tastetissues and may function as receptors for the umami taste sensation(Monastyrskaia et al., (1999) Br. J. Pharmacol., 128:1027-1034; Toyonoet al., (2002) Arch. Histol. Cytol., 65:91-96). Thus positive allostericmodulators of mGluR4 may be useful as taste agents, flavour agents,flavour enhancing agents or food additives.

There is anatomical evidence that the majority of vagal afferentsinnervating gastric muscle express group III mGluRs (mGluR4, mGluR6,mGluR7 and mGluR8) and actively transport receptors to their peripheralendings (Page et al., (2005) Gastroenterology, 128:402-10). Recently, itwas shown that the activation of peripheral group III mGluRs inhibitedvagal afferents mechanosensitivity in vitro which translates intoreduced triggering of transient lower oesophageal sphincter relaxationsand gastroesophageal reflux in vivo (Young et al., (2008)Neuropharmacol, 54:965-975).

Labelling for mGluR4 and mGluR8 was abundant in gastric vagal afferentsin the nodose ganglion, at their termination sites in the nucleustractus solitarius and in gastric vagal motoneurons. These data suggestthat positive allosteric modulators of mGluR4 may be an effectivetreatment for gastro-esophageal reflux disease (GERD) and loweresophageal disorders and gastro-intestinal disorders.

International patent publication WO2005/007096 describes mGluR4 receptorpositive allosteric modulator useful, alone or in combination with aneuroleptic agent, for treating or preventing movement disorders.However, none of the specifically disclosed compounds are structurallyrelated to the compounds of the invention.

More recently, new mGluR4 receptor positive allosteric modulators havebeen described: pyrazolo[3,4-d]pyrimidine derivatives (Niswender et al.,(2008) Bioorganic & Medicinal Chemistry Letters, 18(20):5626-5630),functionalized benzylidene hydrazinyl-3-methylquinazoline andbis-2,3-dihydroquinazolin-4(1H)-one (Williams et al., (2009) Bioorganic& Medicinal Chemistry Letters, 19:962-966) and heterobiarylamides(Engers et al, (2009) Journal of Medicinal Chemistry, 52 (14),4115-4118). Niswender et al., described(±)-cis-2-(3,5-dichlorophenylcarbamoyl)cyclohexane carboxylic acid((2008) Molecular Pharmacology, 74(5):1345-1358), as a positiveallosteric modulator of mGluR4 also having agonist activity. Thismoderately active molecule has demonstrated evidence of efficacyfollowing icy injection in rat models of Parkinson's disease.International patent publications WO2009/070871 and WO2009/010455 (UKpriority application: GB2455111) have mentioned amido derivatives andnovel heteroaromatic derivatives, respectively, as positive allostericmodulators of metabotropic glutamate receptors. The subject of thelatter case has been examined in the following article East Stephen P.et al., (2010) Expert Opin. Ther. Patents, 20 (3) 441-445. Finally,Williams R. et al., described in (2010) ACS Chemical Neuroscience, 1(6):411-419, the “Re-exploration of the PHCCC scaffold”.

The following prior art compounds are only chemical reagents and, to theinventors' knowledge, they are not described as such, or for anypharmaceutical use, in a patent or a scientific publication:

-   [3-Methyl-4-[5-(phenylamino)-1,2,4-thiadiazol-3-yl]-1H-pyrazol-1-yl]phenyl-methanone;-   3-[1-[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-3-methyl-1H-pyrazol-4-yl]-N-phenyl-1,2,4-thiadiazol-5-amine;    and-   [3-Methyl-4-[5-(phenylamino)-1,2,4-thiadiazol-3-yl]-1H-pyrazol-1-yl]-2-thienyl-methanone.

It has now, surprisingly, been found that the compounds of generalFormula (I) show potent activity and selectivity on mGluR4 receptor. Thecompounds of the invention demonstrate advantageous properties overcompounds of the prior art. Improvements have been observed in one ormore of the following characteristics of the compounds of the invention:the potency on the target, the selectivity for the target, thebioavailability, the brain penetration, and the activity in behaviouralmodels.

The present invention relates to a method of treating or preventing acondition in a mammal, including a human, the treatment or prevention ofwhich is affected or facilitated by the neuromodulatory effect of mGluR4modulators. In the case of the treatment of movement disorders such asParkinson's disease, the compounds of the invention can be used alone orin combination with an agent selected from the group consisting of:levodopa, levodopa with a selective extracerebral decarboxylaseinhibitor, carbidopa, entacapone, a COMT inhibitor or a dopamineagonist.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to compounds having metabotropic glutamatereceptor 4 modulator activity. In its most general compound aspect, thepresent invention provides a compound according to Formula (I),

a pharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof and an N-oxide form thereof,wherein:X is selected from N or from C which may further be substituted by A;A radical is selected from the group of hydrogen, halogen, —CN, —OH,—CF₃, —SH, —NH₂ and an optionally substituted radical selected from thegroup of —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl,—(C₂-C₆)alkenyl, —(C₃-C₇)cycloalkyl, —(C₃-C₈)cycloalkenyl,—(C₁-C₆)cyanoalkyl, —(C₁-C₆)alkylene-heteroaryl, —(C₁-C₆)alkylene-aryl,—(C₁-C₆)alkylene-heterocycle, —(C₁-C₆)alkylene-cycloalkyl, aryl,heteroaryl, heterocycle, —(C₀-C₆)alkyl-OR¹, —O—(C₂-C₆)alkylene-OR¹,—NR¹(C₂-C₆)alkylene-OR², —(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—O—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, —NR¹—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—(C₁-C₆)haloalkylene-OR %-(C₁-C₆)haloalkylene-NR¹R²,—(C₃-C₆)alkynyl-OR¹, —(C₃-C₆)alkynyl-NR¹R², —(C₃-C₆)alkenyl-OR¹,—(C₃-C₆)alkenyl-NR¹R², —(C₀-C₆)alkyl-S—R¹, —O—(C₂-C₆)alkylene-S—R¹,—NR¹—(C₂-C₆)alkylene-S—R², —(C₀-C₆)alkyl-S(═O)—R¹, —O—(C₁-C₆)alkylene-S(═O)—R¹, —NR¹—(C₁-C₆)alkylene-S (═O)—R², —(C₀-C₆)alkyl-S(═O)₂—R¹,—O—(C₁-C₆)alkylene-S(═O)₂—R¹, —NR¹—(C₁-C₆)alkylene-S(═O)₂—R²,—(C₀-C₆)alkyl-NR¹R², —O—(C₂-C₆)alkylene-NR¹R²,—NR¹—(C₂-C₆)alkylene-NR²R³, —(C₀-C₆)alkyl-S(═O)₂NR¹R²,—O—(C₁-C₆)alkylene-S(═O)₂NR¹R², —NR¹—(C₁-C₆)alkylene-S(═O)₂NR²R³,—(C₀-C₆)alkyl-NR¹—S(═O)₂R², —O—(C₂-C₆)alkylene-NR¹—S(═O)₂R²,—NR¹—(C₂-C₆)alkylene-NR²—S(═O)₂R³, —(C₀-C₆)alkyl-C(═O)—NR¹R²,—O—(C₁-C₆)alkylene-C(═O)—NR¹R², —NR¹—(C₁-C₆)alkylene-C(═O)—NR²R³,—(C₀-C₆)alkyl-NR¹C(═O)—R², —O—(C₂-C₆)alkylene-NR¹C(═O)—R²,—NR¹—(C₂-C₆)alkylene-NR²C(═O)—R³, —(C₀-C₆)alkyl-C(═O)—R¹,—O—(C₁-C₆)alkylene-C(═O)—R¹, —NR¹—(C₁-C₆)alkylene-C(═O)—R²,—(C₀-C₆)alkyl-NR¹—C(═O)—NR²R³, —O—(C₂-C₆)alkylene-NR¹—C(═O)—NR²R³,—NR¹—(C₂-C₆)alkylene-NR²—C(═O)—NR³R⁴ and —(C₀-C₆)alkyl-NR¹—C(═S)—NR²R³;R¹, R², R³ and R⁴ are each independently hydrogen or an optionallysubstituted radical selected from the group of —(C₁-C₆)haloalkyl,—(C₁-C₆)alkyl, —(C₁-C₆)cyanoalkyl, —(C₃-C₇)cycloalkyl,—(C₄-C₁₀)alkylene-cycloalkyl, heteroaryl, —(C₁-C₆)alkylene-heteroaryl,—(C₁-C₆)alkylene-heterocycle, aryl, heterocycle and—(C₁-C₆)alkylene-aryl;Any two radicals of R(R¹, R², R³ or R⁴) may be taken together to form anoptionally substituted 3 to 10 membered carbocyclic or heterocyclicring;n is an integer ranging from 1 to 2;(B)_(n) radicals are each independently selected from the group ofhydrogen, halogen, —CN, —OH, —CF₃, —SH, —NH₂ and an optionallysubstituted radical selected from the group of —(C₁-C₆)alkyl,—(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl, —(C₂-C₆)alkenyl, —(C₃-C₇)cycloalkyl,—(C₃-C₈)cycloalkenyl, —(C₁-C₆)cyanoalkyl, —(C₁-C₆)alkylene-heteroaryl,—(C₁-C₆)alkylene-aryl, —(C₁-C₆)alkylene-heterocycle,—(C₁-C₆)alkylene-cycloalkyl, aryl, heteroaryl, heterocycle,—(C₀-C₆)alkyl-OR⁵, —O—(C₂-C₆)alkylene-OR⁵, —NR⁵(C₂-C₆)alkylene-OR⁶,—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, —O—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—NR^(S)—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, —(C₁-C₆)haloalkylene-OR⁵,—(C₁-C₆)haloalkylene-NR⁵R⁶, —(C₃-C₆)alkynyl-OR⁵, —(C₃-C₆)alkynyl-NR⁵R⁶,—(C₃-C₆)alkenyl-OR⁵, —(C₃-C₆)alkenyl-NR⁵R⁶, —(C₀-C₆)alkyl-S—R⁵,—O—(C₂-C₆)alkylene-S—R⁵, —NR⁵⁴C₂-C₆)alkylene-S—R⁶,—(C₀-C₆)alkyl-S(═O)—R⁵, —O—(C₁-C₆)alkylene-S(═O)—R⁵,—NR⁵—(C₁-C₆)alkylene-S(═O)—R⁶, —(C₀-C₆)alkyl-S(═O)₂—R⁵,—O—(C₁-C₆)alkylene-S(═O)₂—R⁵, —NR⁵—(C₁-C₆)alkylene-S(═O)₂—R⁶,—(C₀-C₆)alkyl-NR⁵R⁶, —O—(C₂-C₆)alkylene-NR⁵R⁶,—NR⁵—(C₂-C₆)alkylene-NR⁶R⁷, —(C₀-C₆)alkyl-S(═O)₂NR⁵R⁶,—O—(C₁-C₆)alkylene-S(═O)₂NR⁵R⁶, —NR⁵—(C₁-C₆)alkylene-S(═O)₂NR⁶R⁷,—(C₀-C₆)alkyl-NR⁵—S(═O)₂R⁶, —O—(C₂-C₆)alkylene-NR⁵—S(═O)₂R⁶,—NR⁵—(C₂-C₆)alkylene-NR⁶—S(═O)₂R⁷, —(C₀-C₆)alkyl-C(═O)—NR⁵R⁶,—O—(C₁-C₆)alkylene-C(═O)—NR⁵R⁶, —NR⁵—(C₁-C₆)alkylene-C(═O)—NR⁶R⁷,—(C₀-C₆)alkyl-NR⁵C(═O)—R⁶, —O—(C₂-C₆)alkylene-NR⁵C(═O)—R⁶,—NR⁵—(C₂-C₆)alkylene-NR⁶C(═O)—R⁷, —(C₀-C₆)alkyl-C(═O)—R⁵,—O—(C₁-C₆)alkylene-C(═O)—R⁵, —NR⁵—(C₁-C₆)alkylene-C(═O)—R⁶,—(C₀-C₆)alkyl-NR⁵—C(═O)—NR⁶R⁷, —O—(C₂-C₆)alkylene-NR⁵—C(═O)—NR⁶R⁷,—NR⁵—(C₂-C₆)alkylene-NR⁶—C(═O)—NR⁷R⁸ and —(C₀-C₆)alkyl-NR⁵—C(═S)—NR⁶R⁷;R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen or an optionallysubstituted radical selected from the group of —(C₁-C₆)haloalkyl,—(C₁-C₆)alkyl, —(C₁-C₆)cyanoalkyl, —(C₃-C₇)cycloalkyl,—(C₄-C₁₀)alkylene-cycloalkyl, heteroaryl, —(C₁-C₆)alkylene-heteroaryl,—(C₁-C₆)alkylene-heterocycle, aryl, heterocycle and—(C₁-C₆)alkylene-aryl;M is selected from an optionally substituted 3 to 10 membered ringselected from the group of aryl, heteroaryl, heterocyclic andcycloalkyl;P is selected from the group of a hydrogen or an optionally substitutedradical selected from the group of —(C₀-C₆)alkyl-C(═O)—R⁹,—(C₁-C₆)alkyl-CN, —(C₂-C₆)alkyl-S(O)—R⁹, —(C₀-C₆)alkyl-C(═O)NR⁹R¹⁰,—(C₂-C₆)alkyl-NR⁹C(═O)R¹⁰, —(C₀-C₆)alkyl-S(O)₂—R⁹, —(C₀-C₆)alkyl-R⁹,—(C₂-C₆)alkyl-NR⁹R¹⁰, —(C₂-C₆)alkyl-OR⁹ and —(C₂-C₆)alkyl-SR⁹;R⁹ and R¹⁰ are selected from the group of a hydrogen or an optionallysubstituted radical selected from the group of —(C₁-C₆)haloalkyl,—(C₁-C₆)alkyl, —(C₁-C₆)cyanoalkyl, —(C₃-C₇)cycloalkyl,—(C₄-C₁₀)alkylene-cycloalkyl, heteroaryl, —(C₁-C₆)alkylene-heteroaryl,aryl, —(C₁-C₆)alkylene-heterocycle, heterocycle and—(C₁-C₆)alkylene-aryl.

In a more preferred aspect of Formula (I), the invention provides acompound according to Formula (II):

a pharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof and an N-oxide form thereof.

In a more preferred aspect of Formula (II), the invention provides acompound according to Formula (III):

a pharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof and an N-oxide form thereofwherein:B₁ radical is selected from the group of hydrogen, halogen, CF₃ or anoptionally substituted radical selected from the group of —(C₁-C₆)alkyl,—(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl; andM is an optionally substituted heteroaryl.

In a more preferred aspect of Formula (I), the invention provides acompound according to Formula (IV):

a pharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof and an N-oxide form thereof.

In a more preferred aspect of Formula (IV), the invention provides acompound according to Formula (V):

a pharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof and an N-oxide form thereofwherein:B₁ radical is selected from the group of hydrogen, halogen, CF₃ or anoptionally substituted radical selected from the group of —(C₁-C₆)alkyl,—(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl; andM is an optionally substituted heteroaryl.

Particular preferred compounds of the invention are compounds asmentioned in the following list (List of Particular PreferredCompounds), as well as a pharmaceutically acceptable acid or baseaddition salt thereof, a stereochemically isomeric form thereof and anN-oxide form thereof:

-   2-(1H-Pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-4-amine-   5-(1H-Pyrazol-4-yl)-N-(pyridin-2-yl)-1,2,4-thiadiazol-3-amine-   N-(6-Fluoropyridin-2-yl)-2-(1H-pyrazol-4-yl)thiazol-4-amine-   N-(4-Methylpyrimidin-2-yl)-2-(1H-pyrazol-4-yl)thiazol-4-amine-   N-(4-Methoxypyrimidin-2-yl)-2-(1H-pyrazol-4-yl)thiazol-4-amine-   N-(6-Methylpyridin-2-yl)-2-(1H-pyrazol-4-yl)thiazol-4-amine-   2-(1H-Pyrazol-4-yl)-N-(pyrimidin-2-yl)thiazol-4-amine-   N-(Pyridin-2-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazol-4-amine-   2-(3-Cyclopropyl-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-4-amine-   2-(3-Cyclopropyl-1H-pyrazol-4-yl)-N-(pyrimidin-2-yl)thiazol-4-amine    and-   N-(Pyrimidin-2-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazol-4-amine.

DEFINITION OF TERMS

Listed below are definitions of various terms used in the specificationand claims to describe the present invention.

For the avoidance of doubt it is to be understood that in thisspecification “(C₁-C₆)” means a carbon radical having 1, 2, 3, 4, 5 or 6carbon atoms. “(C₀-C₆)” means a carbon radical having 0, 1, 2, 3, 4, 5or 6 carbon atoms. In this specification “C” means a carbon atom, “N”means a nitrogen atom, “O” means an oxygen atom and “S” means a sulphuratom.

In the case where a subscript is the integer 0 (zero) the radical towhich the subscript refers, indicates that the radical is absent, i.e.there is a direct bond between the radicals.

In this specification, unless stated otherwise, the term “bond” refersto a saturated covalent bond. When two or more bonds are adjacent to oneanother, they are assumed to be equal to one bond. For example, aradical -A-B-, wherein both A and B may be a bond, the radical isdepicting a single bond.

In this specification, unless stated otherwise, the term “alkyl”includes both straight and branched chain alkyl radicals and may bemethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl,n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl, i-hexyl or t-hexyl.The term “(C₀-C₃)alkyl” refers to an alkyl radical having 0, 1, 2 or 3carbon atoms and may be methyl, ethyl, n-propyl and i-propyl.

In this specification, unless stated otherwise, the term “alkylene”includes both straight and branched difunctional saturated hydrocarbonradicals and may be methylene, ethylene, n-propylene, i-propylene,n-butylene, i-butylene, s-butylene, t-butylene, n-pentylene,i-pentylene, t-pentylene, neo-pentylene, n-hexylene, i-hexylene ort-hexylene.

In this specification, unless stated otherwise, the term “alkenyl”includes both straight and branched chain alkenyl radicals. The term“(C₂-C₆)alkenyl” refers to an alkenyl radical having 2 to 6 carbon atomsand one or two double bonds, and may be, but is not limited to vinyl,allyl, propenyl, i-propenyl, butenyl, i-butenyl, crotyl, pentenyl,i-pentenyl and hexenyl.

In this specification, unless stated otherwise, the term “alkynyl”includes both straight and branched chain alkynyl radicals. The term(C₂-C₆)alkynyl having 2 to 6 carbon atoms and one or two triple bonds,and may be, but is not limited to ethynyl, propargyl, butynyl,i-butynyl, pentynyl, i-pentynyl and hexynyl.

In this specification, unless stated otherwise, the term “cycloalkyl”refers to an optionally substituted carbocycle containing noheteroatoms, including mono-, bi-, and tricyclic saturated carbocycles,as well as fused ring systems. Such fused ring systems can include onering that is partially or fully unsaturated such as a benzene ring toform fused ring systems such as benzo-fused carbocycles. Cycloalkylincludes such fused ring systems as spirofused ring systems. Examples ofcycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,decahydronaphthalene, adamantane, indanyl, fluorenyl and1,2,3,4-tetrahydronaphthalene and the like. The term “(C₃-C₇)cycloalkyl”may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andthe like.

The term “aryl” refers to an optionally substituted monocyclic orbicyclic hydrocarbon ring system containing at least one unsaturatedaromatic ring. Examples and suitable values of the term “aryl” arephenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indyl, indenyl and thelike.

In this specification, unless stated otherwise, the term “heteroaryl”refers to an optionally substituted monocyclic or bicyclic unsaturated,aromatic ring system containing at least one heteroatom selectedindependently from N, O or S. Examples of “heteroaryl” may be, but arenot limited to thienyl, pyridyl, thiazolyl, isothiazolyl, furyl,pyrrolyl, triazolyl, imidazolyl, oxadiazolyl, oxazolyl, isoxazolyl,pyrazolyl, imidazolonyl, oxazolonyl, thiazolonyl, tetrazolyl,thiadiazolyl, benzoimidazolyl, benzooxazolyl, benzothiazolyl,tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, benzofuryl,benzothiophenyl, thionaphthyl, indolyl, isoindolyl, pyridonyl,pyridazinyl, pyrazinyl, pyrimidinyl, quinolyl, phtalazinyl,naphthyridinyl, quinoxalinyl, quinazolyl, imidazopyridyl,oxazolopyridyl, thiazolopyridyl, imidazopyridazinyl, oxazolopyridazinyl,thiazolopyridazinyl, cynnolyl, pteridinyl, furazanyl, benzotriazolyl,pyrazolopyridinyl and purinyl.

In this specification, unless stated otherwise, the term“alkylene-aryl”, “alkylene-heteroaryl”, “alkylene-heterocycle” and“alkylene-cycloalkyl” refers respectively to a substituent that isattached via the alkyl radical to an aryl, heteroaryl, heterocycle orcycloalkyl radical, respectively. The term “(C₁-C₆)alkylene-aryl”includes aryl-C₁-C₆-alkyl radicals such as benzyl, 1-phenylethyl,2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl,1-naphthylmethyl and 2-naphthylmethyl. The term“(C₁-C₆)alkylene-heteroaryl” includes heteroaryl-C₁-C₆-alkyl radicals,wherein examples of heteroaryl are the same as those illustrated in theabove definition, such as 2-furylmethyl, 3-furylmethyl, 2-thienylmethyl,3-thienylmethyl, 1-imidazolylmethyl, 2-imidazolylmethyl,3-imidazolylmethyl, 2-oxazolylmethyl, 3-oxazolylmethyl,2-thiazolylmethyl, 3-thiazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl,4-pyridylmethyl, 1-quinolylmethyl or the like.

In this specification, unless stated otherwise, the term “heterocycle”refers to an optionally substituted, monocyclic or bicyclic saturated,partially saturated or unsaturated ring system containing at least oneheteroatom selected independently from N, O and S.

In this specification, unless stated otherwise, a 5- or 6-membered ringcontaining one or more atoms independently selected from C, N, O and S,includes aromatic and heteroaromatic rings as well as carbocyclic andheterocyclic rings which may be saturated or unsaturated. Examples ofsuch rings may be, but are not limited to, furyl, isoxazolyl,isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, imidazolidinyl,imidazolinyl, triazolyl, morpholinyl, piperazinyl, piperidyl,piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl,tetrahydropyranyl, tetrahydrothiopyranyl, oxazolidinonyl,thiomorpholinyl, oxadiazolyl, thiadiazolyl, tetrazolyl, phenyl,cyclohexyl, cyclopentyl, cyclohexenyl and cyclopentenyl.

In this specification, unless stated otherwise, a 3- to 10-membered ringcontaining one or more atoms independently selected from C, N, O and S,includes aromatic and heteroaromatic rings as well as carbocyclic andheterocyclic rings which may be saturated or unsaturated. Examples ofsuch rings may be, but are not limited to imidazolidinyl, imidazolinyl,morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl,pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,thiomorpholinyl, tetrahydrothiopyranyl, furyl, pyrrolyl, isoxazolyl,isothiazolyl, oxazolyl, oxazolidinonyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl,imidazolyl, triazolyl, phenyl, cyclopropyl, aziridinyl, cyclobutyl,azetidinyl, oxadiazolyl, thiadiazolyl, tetrazolyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl,cyclooctyl and cyclooctenyl.

In this specification, unless stated otherwise, the term “halo” or“halogen” may be fluoro, chloro, bromo or iodo.

In this specification, unless stated otherwise, the term “haloalkyl”means an alkyl radical as defined above, substituted with one or morehalo radicals. The term “(C₁-C₆)haloalkyl” may include, but is notlimited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyland difluoroethyl. The term “O—C₁-C₆-haloalkyl” may include, but is notlimited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy andfluoroethoxy.

In this specification, unless stated otherwise, the term “haloalkylene”means an alkylene radical as defined above, substituted with one or morehalo radicals. The term “(C₁-C₆)haloalkylene” may include, but is notlimited to, fluoromethylene, difluoromethylene, fluoroethylene anddifluoroethylene. The term “O—C₁-C₆-haloalkylene” may include, but isnot limited to, fluoromethylenoxy, difluoromethylenoxy andfluoroethylenoxy.

In this specification, unless stated otherwise, the term “cyanoalkyl”means an alkyl radical as defined above, substituted with one or morecyano.

In this specification, unless stated otherwise, the term “optionallysubstituted” refers to radicals further bearing one or more substituentswhich may be, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkylene-oxy, mercapto,aryl, heterocycle, halogen, trifluoromethyl, pentafluoroethyl, cyano,cyanomethyl, nitro, amino, amido, amidinyl, carboxyl, carboxamide,(C₁-C₆)alkylene-oxycarbonyl, carbamate, sulfonamide, ester and sulfonyl.

In this specification, unless stated otherwise, the term “solvate”refers to a complex of variable stoichiometry formed by a solute (e.g. acompound of Formula (I)) and a solvent. The solvent is apharmaceutically acceptable solvent as preferably water; such solventmay not interfere with the biological activity of the solute.

In this specification, unless stated otherwise, the term “positiveallosteric modulator of mGluR4” or “allosteric modulator of mGluR4”refers also to a pharmaceutically acceptable acid or base addition saltthereof, a stereochemically isomeric form thereof and an N-oxide formthereof.

Pharmaceutical Compositions

Allosteric modulators of mGluR4 described herein, and thepharmaceutically acceptable salts, solvates and hydrates thereof can beused in pharmaceutical preparations in combination with apharmaceutically acceptable carrier or diluent. Suitablepharmaceutically acceptable carriers include inert solid fillers ordiluents and sterile aqueous or organic solutions. The allostericmodulators of mGluR4 will be present in such pharmaceutical compositionsin amounts sufficient to provide the desired dosage amount in the rangedescribed herein. Techniques for formulation and administration of thecompounds of the instant invention can be found in Remington: theScience and Practice of Pharmacy, 19^(th) edition, Mack Publishing Co.,Easton, Pa. (1995).

The amount of allosteric modulators of mGluR4, administered to thesubject will depend on the type and severity of the disease or conditionand on the characteristics of the subject, such as general health, age,sex, body weight and tolerance to drugs. The skilled artisan will beable to determine appropriate dosages depending on these and otherfactors. Effective dosages for commonly used CNS drugs are well known tothe skilled person. The total daily dose usually ranges from about0.05-2000 mg.

The present invention relates to pharmaceutical compositions whichprovide from about 0.01 to 1000 mg of the active ingredient per unitdose. The compositions may be administered by any suitable route. Forexample orally in the form of capsules and the like, parenterally in theform of solutions for injection, topically in the form of onguents orlotions, ocularly in the form of eye-drops, rectally in the form ofsuppositories, intranasally or transcutaneously in the form of deliverysystem like patches.

For oral administration, the allosteric modulators of mGluR4 thereof canbe combined with a suitable solid or liquid carrier or diluent to formcapsules, tablets, pills, powders, syrups, solutions, suspensions andthe like.

The tablets, pills, capsules, and the like contain from about 0.01 toabout 99 weight percent of the active ingredient and a binder such asgum tragacanth, acacias, corn starch or gelatin; excipients such asdicalcium phosphate; a disintegrating agent such as corn starch, potatostarch, alginic acid, a lubricant such as magnesium stearate; and asweetening agent such as sucrose, lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

For parenteral administration the disclosed allosteric modulators ofmGluR4 can be combined with sterile aqueous or organic media to forminjectable solutions or suspensions. For example, solutions in sesame orpeanut oil, aqueous propylene glycol and the like can be used, as wellas aqueous solutions of water-soluble pharmaceutically-acceptable saltsof the compounds. Dispersions can also be prepared in glycerol, liquidpolyethylene glycols and mixtures thereof in oils. Under ordinaryconditions of storage and use, these preparations contain a preservativeto prevent the growth of microorganisms.

In addition, to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation, for example, subcutaneously orintramuscularly or by intramuscular injection. Thus, for example, as anemulsion in an acceptable oil, or ion exchange resins, or as sparinglysoluble derivatives, for example, as sparingly soluble salts.

Preferably disclosed allosteric modulators of mGluR4 or pharmaceuticalformulations containing these compounds are in unit dosage form foradministration to a mammal. The unit dosage form can be any unit dosageform known in the art including, for example, a capsule, an IV bag, atablet, or a vial. The quantity of active ingredient in a unit dose ofcomposition is an effective amount and may be varied according to theparticular treatment involved. It may be appreciated that it may benecessary to make routine variations to the dosage depending on the ageand condition of the patient. The dosage will also depend on the routeof administration which may be by a variety of routes including oral,aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular,intraperitoneal and intranasal.

Classical treatment of Parkinsonism typically involves the use oflevodopa combined with carbidopa (SINEMET™) or benserazide (MADOPAR™).Dopamine agonists such as bromocriptine (PARLODEL™), lisuride andpergolide (CELANCE™) act directly on dopamine receptors and are alsoused for the treatment of Parkinsonism.

Methods of Synthesis

The compounds according to the invention, in particular the compoundsaccording to the Formula (I), may be prepared by methods known in theart of organic synthesis as set forth in part by the following synthesisschemes. In all of the schemes described below, it is well understoodthat protecting groups for sensitive or reactive groups are employedwhere necessary in accordance with general principles of chemistry.Protecting groups are manipulated according to standard methods oforganic synthesis (Green T. W. and Wuts P. G. M., (1991) ProtectingGroups in Organic Synthesis, John Wiley & Sons). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selection ofprocess as well as the reaction conditions and order of their executionshall be consistent with the preparation of compounds of Formula (I).

The compounds according to the invention may be represented as a mixtureof enantiomers, which may be resolved into the individual pure R- orS-enantiomers. If for instance, a particular enantiomer is required, itmay be prepared by asymmetric synthesis or by derivation with a chiralauxiliary, where the resulting diastereomeric mixture is separated andthe auxiliary group cleaved to provide the pure desired enantiomers.Alternatively, where the molecule contains a basic functional group suchas an amino or an acidic functional group such as carboxyl, thisresolution may be conveniently performed by fractional crystallizationfrom various solvents as the salts of an optical active acid or by othermethods known in the literature (e.g. chiral column chromatography).

Resolution of the final product, an intermediate or a starting materialmay be performed by any suitable method known in the art (Eliel E. L.,Wilen S. H. and Mander L. N., (1984) Stereochemistry of OrganicCompounds, Wiley-Interscience).

Many of the heterocyclic compounds of the invention can be preparedusing synthetic routes well known in the art (Katrizky A. R. and. ReesC. W., (1984) Comprehensive Heterocyclic Chemistry, Pergamon Press).

The product from the reaction can be isolated and purified employingstandard techniques, such as extraction, chromatography, crystallizationand distillation.

The compounds of the invention may be prepared by general route ofsynthesis as disclosed in the following methods.

In one embodiment of the present invention compounds of Formula (I) maybe prepared according to the synthetic sequences illustrated inScheme 1. Pyrazole g1 can be protected (PG: protecting group), forexample by p-methoxybenzyl using standard conditions. Then ester g2 maybe hydrolyzed by classical procedures followed by reaction with oxalylchloride quenched by ammonia to yield an amide which is converted intothioamide g3 using Lawesson's reagent. Then cyclization reaction may beperformed between thioamide g3 and bromoketone g4 in the presence ofpyridine using a solvent such as acetone to yield ethylthiazole-4-carboxylate g5. The ester function after saponification isconverted into amine via Curtius rearrangement using DPPA in thepresence of Et₃N in tBuOH followed by treatment in acidic conditionssuch as HCl to yield g6. Then 4-aminothiazole g6 undergoes coupling withMX using Buchwald conditions such as Pd(OAc)₂ as catalyst, CyPF-tBu asligand, sodium-tert-butoxide as base and DME as solvent. g6 can bedeprotected with classical conditions. Finally, compound g7 can bealkylated, arylated, acylated or sulfonylated using conditions wellknown for people skilled in the art.

In another embodiment of the present invention compounds of Formula (I)may be prepared in accordance with Scheme 2. After protection withp-methoxybenzyl using standard conditions, pyrazole g9 undergoes Suzukicoupling with 3,5-dichlorothiadiazole g10 in the presence of Pd(dppf)Cl₂as catalyst, DIPEA as base and dioxane/water as solvents. Then thesubsequent 3-chloro-1,2,4-thiadiazole g12 may be coupled to amine g11using Buchwald conditions such as Pd₂(dba)₃, as catalyst, Xantphos asligand, sodium-tert-butoxide, cesium carbonate as bases and dioxane,toluene as solvents. g13 can be deprotected with classical conditions toyield aminothiadiazole g14. Finally, compound g14 can be arylated,alkylated, acylated or sulfonylated using conditions well known forpeople skilled in the art.

In another embodiment of the present invention compounds of Formula (I)may be prepared according to the synthetic sequences illustrated inScheme 3. Chloroacetamide g15 can be obtained from the proceduredescribed in Shea et al., (2007) Journal of the American ChemicalSociety, 129:1680-1689. Then, the cyclisation may be performed betweenchloroacetamide g15 and thioamide g3 to yield 4-arylaminothiazole g16which can be deprotected with classical conditions to yield g7. Finally,compound g7 can be alkylated, arylated, acylated or sulfonylated usingconditions well known for people skilled in the art.

EXPERIMENTAL

Unless otherwise noted, all starting materials were obtained fromcommercial suppliers and used without further purification.

Specifically, the following abbreviations may be used in the examplesand throughout the specification.

EtOAc (Ethyl acetate) μL(Microliters) t-BuOH (tert-Butanol) mL(Milliliters) CyPF-tBu mmol (Millimoles) ([Dicyclohexylphosphino-ferrocenyl]ethyl di-t-butyl phophine) DCM (Dichloromethane) M.p.(Melting point) DIPEA (Diisopropyl ethyl NaCl (Sodium chloride) amine)DME (Dimethoxyethane) NaHCO₃ (Sodium hydrogeno- carbonate) DMF(Dimethylformamide) NaOH (Sodium hydroxide) DPPA (DiphenylphosphorylNa₂CO₃ (Sodium carbonate) azide) EtOH (Ethanol) Na₂SO₄ (Sodium sulphate)Et₂O (Diethyl ether) Pd(dppf)Cl₂ (1,1′Bis-(diphenylphos-phino)-ferrocene)-palladiumdi- chloride) Et₃N (Triethyl amine) Pd(dba)₂(Bis(Dibenzylideneacetone)palladium) HCl (Hydrochloric acid) Pd₂(dba)₃(Tris(Dibenzylideneacetone)di- palladium) K₂CO₃ (Potassium carbonate)Pd(OAc)₂ (Palladium(II)acetate) LC-MS (Liquid Chromatography RT(Retention Time) Mass Spectrum) LiOH (Lithium hydroxide) TFA(Trifluoroacetic acid) M (Molar) THF (Tetrahydrofuran) MeOH (Methanol)UPLC-MS (Ultra Performance Liquid Chromatography Mass Spectrum) mg(Milligrams) Xantphos (4,5-Bis(diphenylphos-phino)-9,9-dimethylxanthene) MgSO₄ (Magnesium sulphate)

All references to brine refer to a saturated aqueous solution of NaCl.Unless otherwise indicated, all temperatures are expressed in ° C.(degrees Centigrade). All reactions are conducted not under an inertatmosphere at room temperature unless otherwise noted.

Most of the reaction were monitored by thin-layer chromatography on 0.25mm Merck silica gel plates (60F-254), visualized with UV light. Flashcolumn chromatography was performed on prepacked silica gel cartridges(15-40 μM, Merck).

Melting point determination was performed on a Buchi B-540 apparatus.

EXAMPLES Example 1 2-(1H-Pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-4-amine(Final Compound 1-1) Ethyl 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate

According to Scheme 1 Step 1: K₂CO₃ (803 mmol, 111 g) followed by1-(chloromethyl)-4-methoxybenzene (562 mmol, 76.0 mL) were added slowlyto a solution of ethyl 1H-pyrazole-4-carboxylate (535 mmol, 75.0 g) inacetonitrile (500 mL) at room temperature. Then the suspension washeated under reflux for 4 hours. At room temperature, the reactionmixture was filtered, was concentrated under reduced pressure and wasslurried in petroleum ether to yield ethyl1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (530 mmol, 138 g, 99%) asa white solid.

UPLC-MS: RT=1.01 min; MS m/z ES⁺=261.

1-(4-Methoxybenzyl)-1H-pyrazole-4-carboxylic acid

According to Scheme 1 Step 2: A solution of LiOH (358 mmol, 15.3 g) inwater (2 M) was added at room temperature to a solution of1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (143 mmol, 37.2 g) inTHF/MeOH (1:1, 400 mL) and the reaction mixture was heated at 60° C.overnight. After evaporation of THF and MeOH, a solid was filtered,water (150 mL) was added and the aqueous phase was extracted with Et₂O.The aqueous phase was then acidified with a solution of HCl 1 M untilpH=1-2 and extracted with DCM. The organic phase was washed with brine,was dried over MgSO₄, was filtered and was concentrated under reducedpressure to yield 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid (138mmol, 32.1 g, 97%) as a pale yellow solid. The crude product was usedwithout further purification.

UPLC-MS: RT=0.77 min; MS m/z ES⁻=231.

1-(4-Methoxybenzyl)-1H-pyrazole-4-carboxamide

According to Scheme 1 Step 3: Oxalyl chloride (227 mmol, 19.5 mL) andthree drops of DMF were added to a solution of1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid (114 mmol, 26.4 g) inDCM (227 mL). The reaction mixture was stirred for 30 minutes at roomtemperature. After evaporation of the solvent, dry DCM (100 mL) wasadded to the crude residue. The acyl chloride solution was then added at0° C. to a solution of ammonia in water (454 mmol, 23.4 g) and thereaction mixture was stirred overnight. After filtration and evaporationto dryness, 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxamide (109 mmol,25.1 g, 96%) was obtained as a colorless solid. The crude product wasused without further purification.

UPLC-MS: RT=0.68 min; MS m/z ES⁺=232.

1-(4-Methoxybenzyl)-1H-pyrazole-4-carbothioamide

According to Scheme 1 Step 4: A solution of1-(4-methoxybenzyl)-1H-pyrazole-4-carboxamide (109 mmol, 25.1 g) andLawesson's reagent (109 mmol, 43.9 g) in CHCl₃/toluene (1:1, 136 mL) wasstirred at 85° C. for 12 hours. The reaction mixture was evaporated andthe residue was recrystallized in EtOAc/pentane to yield 13.8 g of1-(4-methoxybenzyl)-1H-pyrazole-4-carbothioamide. The mother liquorswere evaporated and the crude residue was purified by flashchromatography over silica gel using DCM/EtOAc (100:0 to 70:30) to yield1-(4-methoxybenzyl)-1H-pyrazole-4-carbothioamide (94.6 mmol, 23.4 g,87%) as a beige solid.

UPLC-MS: RT=0.72 min; MS m/z ES⁺=248.

Ethyl 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxylate

According to Scheme 1 Step 5: A solution of1-(4-methoxybenzyl)-1H-pyrazole-4-carbothioamide (26.7 mmol, 6.60 g),ethyl 3-bromo-2-oxopropanoate (29.4 mmol, 4.62 mL) and pyridine (29.4mmol, 2.37 mL) in acetone (53 mL) was stirred at room temperature for 2hours and at 45° C. for 52 hours. After evaporation, the crude residuewas partitioned between EtOAc and a saturated solution of Na₂CO₃. Theaqueous phase was extracted with EtOAc and then with DCM. The organicphase was washed with brine, was dried over MgSO₄, was filtered and wasconcentrated under reduced pressure. The crude residue was purified byflash chromatography over silica gel using DCM/EtOAc (100:0 to 70:30) toyield ethyl2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxylate (15.4mmol, 5.28 g, 58%) as a dark oil.

UPLC-MS: RT=0.96 min; MS m/z ES⁺=344.

2-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxylic acid

According to Scheme 1 Step 6: A solution of NaOH (38.4 mmol, 12.8 mL) inwater (3 M) was added at 0° C. to a solution of ethyl2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxylate (15.4mmol, 5.28 g) in EtOH (38 mL) and the reaction mixture was heated at 50°C. overnight. After evaporation of the solvent, the crude residue waspartitioned between a solution of NaOH (1 M) and EtOAc. Afterextraction, the organic phase was washed with a solution of NaOH (1 M).The aqueous phase was then acidified and the beige precipitate formedwas filtered off, washed with water and dried to yield2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxylic acid (13.6mmol, 4.29 g, 88%) as a beige solid.

UPLC-MS: RT=0.73 min; MS m/z ES⁺=316.

tert-Butyl 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-4-ylcarbamate

According to Scheme 1 Step 7: DPPA (16.3 mmol, 3.52 mL) and Et₃N (15.0mmol, 2.10 mL) were added to a solution of2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxylic acid (13.6mmol, 4.29 g) in tBuOH (34 mL) and the reaction mixture was stirred at80° C. for 12 hours. After evaporation of the solvent, the crude residuewas partitioned between DCM and a 10% citric acid solution. The organicphase was washed with a saturated solution of NaHCO₃ and with brine, wasdried over MgSO₄, was filtered and was concentrated. The resulting crudeproduct was purified by flash chromatography over silica gel usingDCM/EtOAc (100:0 to 90:10) as eluent to yield after evaporationtert-butyl 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-4-ylcarbamate(9.21 mmol, 3.56 g, 68%) as a beige solid.

UPLC-MS: RT=1.09 min; MS m/z ES⁺=387.

2-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)thiazol-4-amine

According to Scheme 1 Step 8: A solution of tert-butyl2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-4-ylcarbamate (8.95 mmol,3.46 g) and HO/dioxane (4 M, 90 mmol, 32.4 mL) in dioxane (20 mL) wasstirred at room temperature for 12 hours and after addition of one dropof water for 2 hours at 60° C. After evaporation of the solvent, thecrude residue was partitioned between Et₂O and water. The organic phasewas washed with a solution of HCl (1 M). The aqueous phase was basifiedand extracted with DCM. The organic phase was dried over MgSO₄, wasfiltered and was concentrated to yield after evaporation2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-4-amine (8.94 mmol, 2.56g, 100%) as a dark oil.

UPLC-MS: RT=0.77 min; MS m/z ES⁺=287.

N-(2-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)thiazol-4-yl)pyridin-2-amine

According to Scheme 1 Step 9: A solution of2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-4-amine (0.70 mmol, 200mg), 2-chloropyridine (0.70 mmol, 65.6 μL), CyPF-tBu (52 μmol, 29.4 mg),Pd(OAc)₂ (52 μmol, 11.8 mg) and sodium tert-butoxide (0.98 mmol, 71.4mg) in DME (698 μL) was stirred at 80° C. for 12 hours under nitrogen ina microwave tube. After filtration through celite, the resulting crudeproduct was purified by flash chromatography over silica gel usingDCM/EtOH/NH₃ (100:0:0 to 95:4.5:0.5) as eluent to affordN-(2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-4-yl)pyridin-2-amine(0.39 mmol, 144 mg, 57%).

UPLC-MS: RT=2.02 min; MS m/z ES⁺=364.

2-(1H-Pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-4-amine

According to Scheme 1 Step 10: A solution ofN-(2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-4-yl)pyridin-2-amine(0.39 mmol, 143 mg) in TFA (2 mL) was microwaved for 10 minutes at 120°C. The reaction mixture was neutralized with a solution of NaOH (1 M)and was extracted with DCM. The organic phase was dried over MgSO₄, wasfiltered and was concentrated. The resulting crude product was purifiedby flash chromatography over silica gel using DCM/EtOH/NH₃ (100:0:0 to90:9:1) as eluent to yield2-(1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-4-amine (0.24 mmol, 58 mg,61%) as an orange solid.

M.p.: 209-210° C.; UPLC-MS: RT=1.04 min; MS m/z ES⁺=244.

Example 2 5-(1H-Pyrazol-4-yl)-N-(pyridin-2-yl)-1,2,4-thiadiazol-3-amine(Final Compound 1-2)1-(4-Methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

According to Scheme 2 Step 1: A suspension of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (25.8 mmol,5.00 g), 1-(chloromethyl)-4-methoxybenzene (25.8 mmol, 3.49 mL) andK₂CO₃ (25.8 mmol, 3.56 g) in acetonitrile (40 mL) was heated at 80° C.for 5 hours. After filtration over celite, the filtrate was evaporatedand the resulting crude product was purified by flash chromatographyover silica gel using EtOAc/cyclohexane (90:10 to 70:30) as eluent toafford1-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(24.2 mmol, 7.61 g, 94%) as a colorless solid.

UPLC-MS: RT=1.02 min; MS m/z ES⁺=315.

5-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)-3-chloro-1,2,4-thiadiazole

According to Scheme 2 Step 2: A solution of Pd(dppf)Cl₂ (0.64 mmol, 526mg),1-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(6.45 mmol, 2.03 g), 3,5-dichloro-1,2,4-thiadiazole (6.45 mmol, 1.00 g)and DIPEA (12.9 mmol, 2.20 mL) in dioxane/water (1:1, 32 mL) was stirredat 80° C. for 30 minutes under microwave irradiation. The reactionmixture was filtered over celite and washed with DCM. The organic phasewas dried over MgSO₄, was filtered and was concentrated. The resultingcrude product was purified by flash chromatography over silica gel usingDCM/cyclohexane (50/50 to 100:0) then DCM/EtOH (100/0 to 90:10) aseluent to yield after evaporation5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-3-chloro-1,2,4-thiadiazole (3.55mmol, 1.09 g, 55%) as a beige oil.

UPLC-MS: RT=1.09 min; MS m/z ES⁺=307.

N-(5-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)-1,2,4-thiadiazol-3-yl)pyridin-2-amine

According to Scheme 2 Step 3: A solution of5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-3-chloro-1,2,4-thiadiazole (0.81mmol, 250 mg), 2-aminopyridine (1.06 mmol, 100 mg), Xantphos (36 mmol,20.7 mg), Pd₂(dba)₃ (16 mmol, 15 mg) and cesium carbonate (0.88 mmol,1.14 g) in toluene (8 mL) was stirred at 100° C. for 43 hours undernitrogen in a microwave tube. 0.1 Eq of Pd/L was added and the reactionmixture was stirred at 100° C. for 16 hours. Then 0.2 eq of Pd/L and 1.3eq of 2-aminopyridine were added and the reaction mixture was stirred at100° C. for 24 hours. After filtration through celite and evaporation,the resulting crude product was purified by SCX column with MeOH/AcOH(90:10) then MeOH and DCM/MeOH/NH₃ (90:9:1) and finally by semiprep UPLCto affordN-(5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-1,2,4-thiadiazol-3-yl)pyridin-2-amine(0.30 mmol, 110 mg, 37%).

UPLC-MS: RT=0.83 min; MS m/z ES⁺=365.

5-(1H-Pyrazol-4-yl)-N-(pyridin-2-yl)-1,2,4-thiadiazol-3-amine

According to Scheme 2 Step 4: A solution ofN-(5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-1,2,4-thiadiazol-3-yl)pyridin-2-amine(69 mmol, 25 mg) in TFA (686 μL) was microwaved for 5 minutes at 120° C.The reaction mixture was neutralized with a solution of NaOH (1 M) andwas extracted with DCM. The organic phase was dried over MgSO₄, wasfiltered and was concentrated. The resulting crude product was purifiedby flash chromatography over silica gel using DCM/EtOH/NH₃ (100:0:0 to90:9:1) as eluent to yield5-(1H-pyrazol-4-yl)-N-(pyridin-2-yl)-1,2,4-thiadiazol-3-amine (13 mmol,3.3 mg, 19%) as a yellow solid.

UPLC-MS: RT=0.41 min; MS m/z ES⁺=245.

Example 3N-(Pyridin-2-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazol-4-amine(Final Compound 1-8)2-(1-(4-Methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-4-amine

According to Scheme 3 Step 1: A solution of2-chloro-N-(pyridin-2-yl)acetamide hydrochloride (0.48 mmol, 99 mg),1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-4-carbothioamide(0.48 mmol, 150 mg) in DCM (2.5 mL) was stirred under reflux for 5 days.The crude mixture was evaporated to dryness and was purified by flashchromatography over silica gel using DCM/EtOH/NH₃ (100:0:0 to97:2.7:0.3) as eluent to yield2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-4-amine(0.22 mmol, 94 mg, 35%).

UPLC-MS: RT=0.87 min; MS m/z ES⁺=432.

N-(Pyridin-2-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazol-4-amine

According to Scheme 3 Step 2: A solution of2-(1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-4-amine(0.22 mmol, 94 mg) in TFA (1 mL) was stirred under microwave heating at140° C. during 5 minutes then at 150° C. during 5 minutes. The solutionwas dropwise poured onto a saturated aqueous solution of Na₂CO₃ andfiltered. The crude compound was purified by flash chromatography oversilica gel using DCM/EtOH/NH₃ (100:0:0 to 93:6.3:0.7) as eluent to yieldN-(pyridin-2-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazol-4-amine(96 mmol, 30 mg, 44%) as a slightly orange solid.

M.p.: 204-206° C.; UPLC-MS: RT=0.56 min; MS m/z ES⁺=312.

The compounds in the following Table have been synthezised according tothe same methods as previous examples 1 to 3, as denoted in the columndenoted as “Exp. nr”. The compounds denoted with the asterisk have beenexemplified in the Examples.

TABLE 1 Compounds prepared according to the Examples.

Co. nr. Exp nr.

1-1* 1

1-2* 2

1-3 1

1-4 1

1-5 1

1-6 1

1-7 1

1-8* 3

1-9 3

1-10 3

1-11 3

UPLC-MS Method:

UPLC-MS were recorded on Waters ACQUITY UPLC with the followingconditions: Reversed phase UPLC was carried out on BEH-C18 cartridge(1.7 μm, 2.1×50 mm) from Waters, with a flow rate of 0.8 mL/min. Thegradient conditions used are: 90% A (water+0.1% of formic acid), 10% B(acetonitrile+0.1% of formic acid) to 100% B at 1.3 minutes, kept until1.6 minutes and equilibrated to initial conditions at 1.7 minutes until2.0 minutes. Injection volume 5 μL. ES MS detector was used, acquiringboth in positive and negative ionization modes.

All mass spectra were taken under electrospray ionisation (ESI) methods.

TABLE 2 Physico-chemical data for some compounds (nd = not determined).Melting MW Co. Nr point (° C.) (theor) [MH⁺] RT (min) 1-1 207-209 243.29244 0.54 1-2 nd 244.28 245 0.41 1-3 238-240 261.28 262 0.83 1-4 230-232258.30 259 0.70 1-5 250-252 274.3 275 0.59 1-6 nd 257.31 258 0.45 1-7217 (dec) 244.28 245 0.63 1-8 204-206 311.29 312 0.56 1-9  141.3 283.35284 0.56  1-10 241 284.34 285 0.79  1-11 nd 312.27 313 0.85

Pharmacology

The compounds provided in the present invention are positive allostericmodulators of mGluR4. As such, these compounds do not appear to bind tothe orthosteric glutamate recognition site, and do not activate themGluR4 by themselves. Instead, the response of mGluR4 to a concentrationof glutamate or mGluR4 agonist is increased when compounds of Formula Iare present. Compounds of Formula I are expected to have their effect atmGluR4 by virtue of their ability to enhance the function of thereceptor.

mGluR4 Assay on HEK-Expressing Human mGluR4

The compounds of the present invention are positive allostericmodulators of mGluR4 receptor. Their activity was examined onrecombinant human mGluR4a receptors by detecting changes inintracellular Ca²⁺ concentration, using the fluorescent Ca²⁺-sensitivedye Fluo4-(AM) and a Fluorometric Imaging Plate Reader (FLIPR, MolecularDevices, Sunnyvale, Calif.).

Transfection and Cell Culture

The cDNA encoding the human metabotropic glutamate receptor (hmGluR4),(accession number NM_(—)000841.1, NCBI Nucleotide database browser), wassubcloned into an expression vector containing also the hygromycinresistance gene. In parallel, the cDNA encoding a G protein allowingredirection of the activation signal to intracellular calcium flux wassubcloned into a different expression vector containing also thepuromycin resistance gene. Transfection of both these vectors intoHEK293 cells with PolyFect reagent (Qiagen) according to supplier'sprotocol, and hygromycin and puromycin treatment allowed selection ofantibiotic resistant cells which had integrated stably one or morecopies of the plasmids. Positive cellular clones expressing hmGluR4 wereidentified in a functional assay measuring changes in calcium fluxes inresponse to glutamate or selective known mGluR4 orthosteric agonists andantagonists.

HEK-293 cells expressing hmGluR4 were maintained in media containingDMEM, dialyzed Fetal Calf Serum (10%), Glutamax™ (2 mM), Penicillin (100units/mL), Streptomycin (100 μg/mL), Geneticin (100 μg/mL) andHygromycin-B (40 μg/mL) and puromycin (1 μg/mL) at 37° C./5% CO₂.

Fluorescent Cell Based—Ca²⁺ Mobilization Assay

Human mGluR4HEK-293 cells were plated out 24 hours prior to FLIPR³⁸⁴assay in black-walled, clear-bottomed, poly-L-ornithine-coated 384-wellplates at a density of 25,000 cells/well in a glutamine/glutamate freeDMEM medium containing foetal bovine serum (10%), penicillin (100units/mL) and streptomycin (100 μg/mL) at 37° C./5% CO₂.

On the day of the assay, the medium was aspirated and the cells wereloaded with a 3 μM solution of Fluo4-AM (LuBioScience, Lucerne,Switzerland) in 0.03% pluronic acid. After 1 hour at 37° C./5% CO₂, thenon incorporated dye was removed by washing cell plate with the assaybuffer and the cells were left in the dark at room temperature for sixhours before testing. All assays were performed in a pH 7.4buffered-solution containing 20 mM HEPES, 143 mM NaCl, 6 mM KCl, 1 mMMgSO₄, 1 mM CaCl₂, 0.125 mM sulfapyrazone and 0.1% glucose.

After 10 s of basal fluorescence recording, various concentrations ofthe compounds of the invention were added to the cells. Changes influorescence levels were first monitored for 180 s in order to detectany agonist activity of the compounds. Then the cells were stimulated byan EC₂₅ glutamate concentration for an additional 110 s in order tomeasure enhancing activities of the compounds of the invention. EC₂₅glutamate concentration is the concentration giving 25% of the maximalglutamate response.

The concentration-response curves of representative compounds of thepresent invention were generated using the Prism GraphPad software(Graph Pad Inc, San Diego, USA). The curves were fitted to afour-parameter logistic equation:

(Y=Bottom+(Top−Bottom)/(1+10̂((Log EC ₅₀ −X)*Hill Slope)

allowing the determination of EC₅₀ values.

The Table 3 below represents the mean EC₅₀ obtained from at least threeindependent experiments of selected molecules performed in duplicate.

TABLE 3 Activity data for selected compounds Compound no. Ca²⁺ Flux* 1-1++ 1-2 + 1-3 ++ 1-4 + 1-5 + 1-6 + 1-7 ++ 1-8 + 1-9 ++  1-10 ++  1-11 ++*Table legend: (+): 100 nM < EC₅₀ < 1 μM (++): EC₅₀ < 100 nM

The results shown in Table 3 demonstrate that the compounds described inthe present invention are positive allosteric modulators of human mGluR4receptors. These compounds do not have activity by themselves but theyrather increase the functional activity and/or maximal efficacy ofglutamate or mGluR4 agonist.

Thus, the positive allosteric modulators provided in the presentinvention are expected to increase the effectiveness of glutamate ormGluR4 agonists at mGluR4 receptor. Therefore, these positive allostericmodulators are expected to be useful for treatment of variousneurological and psychiatric disorders associated with glutamatedysfunction described to be treated herein and others that can betreated by such positive allosteric modulators.

The compounds of the invention can be administered either alone, or incombination with other pharmaceutical agents effective in the treatmentof conditions mentioned above.

FORMULATION EXAMPLES

Typical examples of recipes for the formulation of the invention are asfollows:

1. Tablets

Active ingredient 5 to 50 mg Di-calcium phosphate 20 mg Lactose 30 mgTalcum 10 mg Magnesium stearate  5 mg Potato starch ad 200 mg

In this Example, active ingredient can be replaced by the same amount ofany of the compounds according to the present invention, in particularby the same amount of any of the exemplified compounds.

2. Suspension

An aqueous suspension is prepared for oral administration so that each 1milliliter contains 1 to 5 mg of one of the active compounds, 50 mg ofsodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg ofsorbitol and water ad 1 mL.

3. Injectable

A parenteral composition is prepared by stirring 1.5% by weight ofactive ingredient of the invention in 10% by volume propylene glycol andwater.

4. Ointment

Active ingredient 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5 g Whitepetroleum 15 g  Water ad 100 g

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

Reasonable variations are not to be regarded as a departure from thescope of the invention. It will be obvious that the thus describedinvention may be varied in many ways by those skilled in the art.

1. A compound having the Formula (I) wherein:

a pharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof and an N-oxide form thereof,wherein: X is selected from N or from C which may further be substitutedby A; A radical is selected from the group of hydrogen, halogen, —CN,—OH, —CF₃, —SH, —NH₂ and an optionally substituted radical selected fromthe group of —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl,—(C₂-C₆)alkenyl, —(C₃-C₇)cycloalkyl, —(C₃-C₈)cycloalkenyl,—(C₁-C₆)cyanoalkyl, —(C₁-C₆)alkylene-heteroaryl, —(C₁-C₆)alkylene-aryl,—(C₁-C₆)alkylene-heterocycle, —(C₁-C₆)alkylene-cycloalkyl, aryl,heteroaryl, heterocycle, —(C₀-C₆)alkyl-OR¹, —O—(C₂-C₆)alkylene-OR¹,—NR¹(C₂-C₆)alkylene-OR², —(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—O—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, —NR¹—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—(C₁-C₆)haloalkylene-OR¹, —(C₁-C₆)haloalkylene-NR¹R²,—(C₃-C₆)alkynyl-OR¹, —(C₃-C₆)alkynyl-NR¹R², —(C₃-C₆)alkenyl-OR¹,—(C₃-C₆)alkenyl-NR¹R², —(C₀-C₆)alkyl-S—R¹, —O—(C₂-C₆)alkylene-S—R¹,—NR¹—(C₂-C₆)alkylene-S—R², —(C₀-C₆)alkyl-S(═O)—R¹,—O—(C₁-C₆)alkylene-S(═O)—R¹, —NR¹—(C₁-C₆)alkylene-S(═O)—R²,—(C₀-C₆)alkyl-S(═O)₂—R¹, —O—(C₁-C₆)alkylene-S(═O)₂—R¹,—NR¹—(C₁-C₆)alkylene-S(═O)₂—R², —(C₀-C₆)alkyl-NR¹R²,—O—(C₂-C₆)alkylene-NR¹R², —NR¹—(C₂-C₆)alkylene-NR²R³,—(C₀-C₆)alkyl-S(═O)₂NR¹R², —O—(C₁-C₆)alkylene-S(═O)₂NR¹R²,—NR¹—(C₁-C₆)alkylene-S(═O)₂NR²R³, —(C₀-C₆)alkyl-NR¹—S(═O)₂R²,—O—(C₂-C₆)alkylene-NR¹—S(═O)₂R², —NR¹—(C₂-C₆)alkylene-NR²—S(═O)₂R³,—(C₀-C₆)alkyl-C(═O)—NR¹R², —O—(C₁-C₆)alkylene-C(═O)—NR¹R²,—NR¹—(C₁-C₆)alkylene-C(═O)—NR²R³, —(C₀-C₆)alkyl-NR¹C(═O)—R²,—O—(C₂-C₆)alkylene-NR¹C(═O)—R², —NR¹—(C₂-C₆)alkylene-NR²C(═O)—R³,—(C₀-C₆)alkyl-C(═O)—R′, —O—(C₁-C₆)alkylene-C(═O)—R¹,—NR¹—(C₁-C₆)alkylene-C(═O)—R², —(C₀-C₆)alkyl-NR'—C(═O)—NR²R³,—O—(C₂-C₆)alkylene-NR¹—C(═O)—NR²R³, —NR'-(C₂-C₆)alkylene-NR²—C(═O)—NR³R⁴and —(C₀-C₆)alkyl-NR'—C(═S)—NR²R³; R¹, R², R³ and R⁴ are eachindependently hydrogen or an optionally substituted radical selectedfrom the group of —(C₁-C₆)haloalkyl, —(C₁-C₆)alkyl, —(C₁-C₆)cyanoalkyl,—(C₃-C₇)cycloalkyl, —(C₄-C₁₀)alkylene-cycloalkyl, heteroaryl,—(C₁-C₆)alkylene-heteroaryl, —(C₁-C₆)alkylene-heterocycle, aryl,heterocycle and —(C₁-C₆)alkylene-aryl; Any two radicals of R(R¹, R², R³or R⁴) may be taken together to form an optionally substituted 3 to 10membered carbocyclic or heterocyclic ring; n is an integer ranging from1 to 2; (B)_(n) radicals are each independently selected from the groupof hydrogen, halogen, —CN, —OH, —CF₃, —SH, —NH₂ and an optionallysubstituted radical selected from the group of —(C₁-C₆)alkyl,—(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl, —(C₂-C₆)alkenyl, —(C₃-C₇)cycloalkyl,—(C₃-C₈)cycloalkenyl, —(C₁-C₆)cyanoalkyl, —(C₁-C₆)alkylene-heteroaryl,—(C₁-C₆)alkylene-aryl, —(C₁-C₆)alkylene-heterocycle,—(C₁-C₆)alkylene-cycloalkyl, aryl, heteroaryl, heterocycle,—(C₀-C₆)alkyl-OR⁵, —O—(C₂-C₆)alkylene-OR⁵, —NR⁵(C₂-C₆)alkylene-OR⁶,—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, —O—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—NR⁵—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl-OR⁵,—(C₁-C₆)haloalkyl-NR⁵R⁶, —(C₃-C₆)alkynyl-OR⁵, —(C₃-C₆)alkynyl-NR⁵R⁶,—(C₃-C₆)alkenyl-OR⁵, —(C₃-C₆)alkenyl-NR⁵R⁶, —(C₀-C₆)alkyl-S—R⁵,—O—(C₂-C₆)alkylene-S—R⁵, —NR⁵—(C₂-C₆)alkylene-S—R⁶,—(C₀-C₆)alkyl-S(═O)—R⁵, —O—(C₁-C₆)alkylene-S(═O)—R⁵,—NR⁵—(C₁-C₆)alkylene-S(═O)—R⁶, —(C₀-C₆)alkyl-S(═O)₂—R⁵,—O—(C₁-C₆)alkylene-S(═O)₂—R⁵, —NR⁵—(C₁-C₆)alkylene-S(═O)₂—R⁶,—(C₀-C₆)alkyl-NR⁵R⁶, —O—(C₂-C₆)alkylene-NR⁵R⁶,—NR⁵—(C₂-C₆)alkylene-NR⁶R⁷, —(C₀-C₆)alkyl-S(═O)₂NR⁵R⁶,—O—(C₁-C₆)alkylene-S(═O)₂NR⁵R⁶, —NR⁵—(C₁-C₆)alkylene-S(═O)₂NR⁶R⁷,—(C₀-C₆)alkyl-NR⁵—S(═O)₂R⁶, —O—(C₂-C₆)alkylene-NR⁵—S(═O)₂R⁶,—NR⁵—(C₂-C₆)alkylene-NR⁶—S(═O)₂R⁷, —(C₀-C₆)alkyl-C(═O)—NR⁵R⁶,—O—(C₁-C₆)alkylene-C(═O)—NR⁵R⁶, —NR⁵—(C₁-C₆)alkylene-C(═O)—NR⁶R⁷,—(C₀-C₆)alkyl-NR⁵C(═O)—R⁶, —O—(C₂-C₆)alkylene-NR⁵C(═O)—R⁶,—NR⁵—(C₂-C₆)alkylene-NR⁶C(═O)—R⁷, —(C₀-C₆)alkyl-C(═O)—R⁵,—O—(C₁-C₆)alkylene-C(═O)—R⁵, —NR⁵—(C₁-C₆)alkylene-C(═O)—R⁶,—(C₀-C₆)alkyl-NR⁵—C(═O)—NR⁶R⁷, —O—(C₂-C₆)alkylene-NR⁵—C(═O)—NR⁶R⁷,—NR⁵—(C₂-C₆)alkylene-NR⁶—C(═O)—NR⁷R⁸ and —(C₀-C₆)alkyl-NR⁵—C(═S)—NR⁶R⁷;R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen or an optionallysubstituted radical selected from the group of —(C₁-C₆)haloalkyl,—(C₁-C₆)alkyl, —(C₁-C₆)cyanoalkyl, —(C₃-C₇)cycloalkyl,—(C₄-C₁₀)alkylene-cycloalkyl, heteroaryl, —(C₁-C₆)alkylene-heteroaryl,—(C₁-C₆)alkylene-heterocycle, aryl, heterocycle and—(C₁-C₆)alkylene-aryl; M is selected from an optionally substituted 3 to10 membered ring selected from the group of aryl, heteroaryl,heterocyclic and cycloalkyl; P is selected from the group of a hydrogenor an optionally substituted radical selected from the group of—(C₀-C₆)alkyl-C(═O)—R⁹, —(C₁-C₆)alkyl-CN, —(C₂-C₆)alkyl-S(O)—R⁹,—(C₀-C₆)alkyl-C(═O)NR⁹R¹⁰, —(C₂-C₆)alkyl-NR⁹C(═O)R¹⁰,—(C₀-C₆)alkyl-S(O)₂—R⁹, —(C₀-C₆)alkyl-R⁹, —(C₂-C₆)alkyl-NR⁹R¹⁰,—(C₂-C₆)alkyl-OR⁹ and —(C₂-C₆)alkyl-SR⁹; R⁹ and R¹⁰ are selected fromthe group of a hydrogen or an optionally substituted radical selectedfrom the group of —(C₁-C₆)haloalkyl, —(C₁-C₆)alkyl, —(C₁-C₆)cyanoalkyl,—(C₃-C₇)cycloalkyl, —(C₄-C₁₀)alkylene-cycloalkyl, heteroaryl,—(C₁-C₆)alkylene-heteroaryl, —(C₁-C₆)alkylene-heterocycle, aryl,heterocycle and —(C₁-C₆)alkylene-aryl.
 2. A compound according to claim1 having the Formula (II):

a pharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof and an N-oxide form thereof.
 3. Acompound according to claim 2 having the Formula (III):

a pharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof and an N-oxide form thereofwherein: B₁ radical is selected from the group of hydrogen, halogen, CF₃or an optionally substituted radical selected from the group of—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl; and M is anoptionally substituted heteroaryl.
 4. A compound according to claim 1having the Formula (IV):

a pharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof and an N-oxide form thereof.
 5. Acompound according to claim 4 having the Formula (V):

a pharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof and an N-oxide form thereofwherein: B₁ radical is selected from the group of hydrogen, halogen, CF₃or an optionally substituted radical selected from the group of—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl; and M is anoptionally substituted heteroaryl.
 6. A compound according to claims 1to 5, which can exist as optical isomers, wherein said compound iseither the racemic mixture or one or both of the individual opticalisomers.
 7. A compound according to claims 1 to 3 and 6, or according toclaims 1 and 4 to 6, wherein said compound is selected from:2-(1H-Pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-4-amine5-(1H-Pyrazol-4-yl)-N-(pyridin-2-yl)-1,2,4-thiadiazol-3-amineN-(6-Fluoropyridin-2-yl)-2-(1H-pyrazol-4-yl)thiazol-4-amineN-(4-Methylpyrimidin-2-yl)-2-(1H-pyrazol-4-yl)thiazol-4-amineN-(4-Methoxypyrimidin-2-yl)-2-(1H-pyrazol-4-yl)thiazol-4-amineN-(6-Methylpyridin-2-yl)-2-(1H-pyrazol-4-yl)thiazol-4-amine2-(1H-Pyrazol-4-yl)-N-(pyrimidin-2-yl)thiazol-4-amineN-(Pyridin-2-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazol-4-amine2-(3-Cyclopropyl-1H-pyrazol-4-yl)-N-(pyridin-2-yl)thiazol-4-amine2-(3-Cyclopropyl-1H-pyrazol-4-yl)-N-(pyrimidin-2-yl)thiazol-4-amineN-(Pyrimidin-2-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazol-4-amineand a pharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof and an N-oxide form thereof.
 8. Apharmaceutical composition comprising a therapeutically effective amountof a compound according to claims 1 to 7 and a pharmaceuticallyacceptable carrier and/or excipient.
 9. A method of treating orpreventing a condition in a mammal, including a human, the treatment orprevention of which is affected or facilitated by the neuromodulatoryeffect of mG 1uR4 allosteric modulators, comprising administering to amammal in need of such treatment or prevention, an effective amount of acompound/composition according to claims 1 to
 8. 10. A method oftreating or preventing a condition in a mammal, including a human, thetreatment or prevention of which is affected or facilitated by theneuromodulatory effect of mGluR4 positive allosteric modulators,comprising administering to a mammal in need of such treatment orprevention, an effective amount of a compound/composition according toclaims 1 to
 8. 11. A method useful for treating or preventing centralnervous system disorders selected from the group consisting of:addiction, tolerance or dependence; affective disorders, such asdepression and anxiety; psychiatric disease such as psychotic disorders,attention-deficit/hyperactivity disorder and bipolar disorder;Parkinson's disease, memory impairment, Alzheimer's disease, dementia,delirium tremens, other forms of neurodegeneration, neurotoxicity, andischemia, comprising administering to a mammalian patient in need ofsuch treatment or prevention, an effective amount of acompound/composition according to claims 1 to
 8. 12. A method useful fortreating or preventing central nervous system disorders selected fromthe group consisting of: Parkinson's disease and movement disorders suchas bradykinesia, rigidity, dystonia, drug-induced parkinsonism,dyskinesia, tardive dyskinesia, L-DOPA-induced dyskinesia, dopamineagonist-induced dyskinesia, hyperkinetic movement disorders, Gilles dela Tourette syndrome, resting tremor, action tremor, akinesia,akinetic-rigid syndrome, akathisia, athetosis, asterixis, tics, posturalinstability, postencephalitic parkinsonism, muscle rigidity, chorea andchoreaform movements, spasticity, myoclonus, hemiballismus, progressivesupranuclear palsy, restless legs syndrome, and periodic limb movementdisorder, comprising administering to a mammalian patient in need ofsuch treatment or prevention, an effective amount of acompound/composition according to claims 1 to
 8. 13. A method of claim12 comprising administering to a mammalian patient in needs of suchtreatment or prevention, an effective amount of a compound/compositionaccording to claims 1 to 8 in combination with an agent selected fromthe group consisting of: levodopa, levodopa with a selectiveextracerebral decarboxylase inhibitor, carbidopa, entacapone, a COMTinhibitor or a dopamine agonist.
 14. A method useful for treating orpreventing central nervous system disorders selected from the groupconsisting of: cognitive disorders such as delirium, substance-inducedpersisting delirium, dementia, dementia due to HIV disease, dementia dueto Huntington's disease, dementia due to Parkinson's disease,Parkinsonian-ALS demential complex, dementia of the Alzheimer's type,substance-induced persisting dementia, and mild cognitive impairment,comprising administering to a mammalian patient in need of suchtreatment or prevention, an effective amount of a compound/compositionaccording to claims 1 to
 8. 15. A method useful for treating affectivedisorders selected from the group consisting of: anxiety, Agoraphobia,Generalized Anxiety Disorder (GAD), Obsessive-Compulsive Disorder (OCD),Panic Disorder, Posttraumatic Stress Disorder (PTSD), Social Phobia,Other Phobias, Substance-Induced Anxiety Disorder, and acute stressdisorder, comprising administering to a mammalian patient in need ofsuch treatment, an effective amount of a compound/composition accordingto claims 1 to
 8. 16. A method useful for treating or preventing centralnervous system disorders selected from the group consisting of: mooddisorders, Bipolar Disorders (I & II), Cyclothymic Disorder, Depression,Dysthymic Disorder, Major Depressive Disorder, and Substance-InducedMood Disorder, comprising administering to a mammalian patient in needof such treatment or prevention, an effective amount of acompound/composition according to claims 1 to
 8. 17. A method useful fortreating or preventing neurological disorders selected from the groupconsisting of: neurodegeneration, neurotoxicity or ischemia such asstroke, spinal cord injury, cerebral hypoxia, intracranial hematoma,Parkinson's disease, memory impairment, Alzheimer's disease, dementia,and delirium tremens, comprising administering to a mammalian patient inneed of such treatment or prevention, an effective amount of acompound/composition according to claims 1 to
 8. 18. A method useful fortreating or preventing inflammatory central nervous system disordersselected from the group consisting of: multiple sclerosis forms such asbenign multiple sclerosis, relapsing-remitting multiple sclerosis,secondary progressive multiple sclerosis, primary progressive multiplesclerosis, and progressive-relapsing multiple sclerosis, comprisingadministering to a mammalian patient in need of such treatment orprevention, an effective amount of a compound/composition according toclaims 1 to
 8. 19. A method useful for treating or preventing migraine,comprising administering to a mammalian patient in need of suchtreatment or prevention, an effective amount of a compound/compositionaccording to claims 1 to
 8. 20. A method useful for treating orpreventing epilepsy and tremor, temporal lobe epilepsy, epilepsysecondary to another disease or injury such as chronic encephalitis,traumatic brain injury, stroke or ischemia, comprising administering toa mammalian patient in need of such treatment or prevention, aneffective amount of a compound/composition according to claims 1 to 8.21. A method useful for treating or preventing inflammation and/orneurodegeneration resulting from traumatic brain injury, stroke,ischemia, spinal cord injury, cerebral hypoxia or intracranial hematoma,comprising administering to a mammalian patient in need of suchtreatment or prevention, an effective amount of a compound/compositionaccording to claims 1 to
 8. 22. A method useful for treating orpreventing sensory, motor or cognitive symptoms resulting from traumaticbrain injury, stroke, ischemia, spinal cord injury, cerebral hypoxia orintracranial hematoma, comprising administering to a mammalian patientin need of such treatment or prevention, an effective amount of acompound/composition according to claims 1 to
 8. 23. A method useful fortreating medulloblastomas, comprising administering to a mammalianpatient in need of such treatment, an effective amount of acompound/composition according to claims 1 to
 8. 24. A method useful fortreating or preventing inflammatory or neuropathic pain, comprisingadministering to a mammalian patient in need of such treatment,prevention, an effective amount of a compound/composition according toclaims 1 to
 8. 25. A method useful for treating, preventing,ameliorating, controlling or reducing the risk of various metabolicdisorders associated with glutamate dysfunction, comprisingadministering to a mammalian patient in need of such treatment orprevention, amelioration, control or reduction of risk, an effectiveamount of a compound/composition according to claims 1 to
 8. 26. Amethod useful for treating or preventing type 2 diabetes, comprisingadministering to a mammalian patient in need of such treatment orprevention, an effective amount of a compound/composition according toclaims 1 to
 8. 27. A method useful for treating or preventing diseasesor disorders of the retina, retinal degeneration or maculardegeneration, comprising administering to a mammalian patient in need ofsuch treatment or prevention, an effective amount of acompound/composition according to claims 1 to
 8. 28. A method useful fortreating or preventing diseases or disorders of the gastrointestinaltract including gastro-esophageal reflux disease (GERD), loweresophageal sphincter diseases or disorders, diseases of gastrointestinalmotility, colitis, Crohn's disease or irritable bowel syndrome (IBS),comprising administering to a mammalian patient in need of suchtreatment or prevention, an effective amount of a compound/compositionaccording to claims 1 to
 8. 29. Use of a compound according to claims 1to 7 in the manufacture of a medicament for a use as defined in any ofclaims 9 to
 28. 30. Use of a compound according to claims 1 to 7 toprepare a tracer for imaging a metabotropic glutamate receptor.
 31. Useof a compound according to claims 1 to 7 as a taste agent, flavouragent, flavour enhancing agent or a food or beverage additive.
 32. Acompound according to claims 1 to 7 or a composition according to claim8 for a use in a treatment or prevention as defined in any of claims 9to 14, 16 to 22, 24 and 26 to
 28. 33. A compound according to claims 1to 7 or a composition according to claim 8 for a use as defined in claim25.
 34. A compound according to claims 1 to 7 or a composition accordingto claim 8 for a use in a treatment as defined in any of claims 15 and23.